Screening for cystic fibrosis-related diabetes: a systematic review

Transcription

1 Health Technology Assessment 2012; Vol. 16: No. 24 ISSN Screening for cystic fibrosis-related diabetes: a systematic review N Waugh, P Royle, I Craigie, V Ho, L Pandit, P Ewings, A Adler, P Helms and C Sheldon May /hta16240 Health Technology Assessment NIHR HTA programme

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3 Screening for cystic fibrosis-related diabetes: a systematic review N Waugh, 1,3 * P Royle, 1,3 I Craigie, 4 V Ho, 1 L Pandit, 1 P Ewings, 5 A Adler, 6 P Helms 2 and C Sheldon 7 1 Department of Public Health and 2 Department of Child Health, University of Aberdeen, Aberdeen, UK 3 Warwick Evidence, Warwick Medical School, Warwick, UK 4 Childrens Diabetes Service, Royal Hospital for Sick Children, Glasgow, UK 5 Research Design Service, Musgrave Park Hospital, Taunton, UK 6 Addenbrookes Hospital, Cambridge, UK 7 Royal Devon and Exeter Hospital, Exeter, UK *Corresponding author Declared competing interests of authors: none Published May 2012 DOI: /hta16240 This report should be referenced as follows: Waugh N, Royle P, Craigie I, Ho V, Pandit L, Ewings P, et al. Screening for cystic fibrosis-related diabetes: a systematic review. Health Technol Assess 2012;16(24). Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Clinical Medicine.

4 ii NIHR Health Technology Assessment programme The Health Technology Assessment (HTA) programme, part of the National Institute for Health Research (NIHR), was set up in It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. Health technologies are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care. The research findings from the HTA programme directly influence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in that they form a key component of the National Knowledge Service. The HTA programme is needs led in that it fills gaps in the evidence needed by the NHS. There are three routes to the start of projects. First is the commissioned route. Suggestions for research are actively sought from people working in the NHS, from the public and consumer groups and from professional bodies such as royal colleges and NHS trusts. These suggestions are carefully prioritised by panels of independent experts (including NHS service users). The HTA programme then commissions the research by competitive tender. Second, the HTA programme provides grants for clinical trials for researchers who identify research questions. These are assessed for importance to patients and the NHS, and scientific rigour. Third, through its Technology Assessment Report (TAR) call-off contract, the HTA programme commissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring together evidence on the value of specific technologies. Some HTA research projects, including TARs, may take only months, others need several years. They can cost from as little as 40,000 to over 1 million, and may involve synthesising existing evidence, undertaking a trial, or other research collecting new data to answer a research problem. The final reports from HTA projects are peer reviewed by a number of independent expert referees before publication in the widely read journal series Health Technology Assessment. Criteria for inclusion in the HTA journal series Reports are published in the HTA journal series if (1) they have resulted from work for the HTA programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors. Reviews in Health Technology Assessment are termed systematic when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others. The research reported in this issue of the journal was commissioned by the HTA programme as project number 07/45/05. The contractual start date was in July The draft report began editorial review in October 2011 and was accepted for publication in February As the funder, by devising a commissioning brief, the HTA programme specified the research question and study design.the authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health. Editor-in-Chief: Professor Tom Walley CBE Series Editors: Dr Martin Ashton-Key, Professor Aileen Clarke, Dr Tom Marshall, Professor John Powell, Dr Rob Riemsma and Professor Ken Stein Associate Editor: Dr Peter Davidson Editorial Contact: edit@southampton.ac.uk ISSN (Print) ISSN (Online) ISSN (DVD) Queen s Printer and Controller of HMSO This work was produced by Waugh et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) ( publicationethics.org/). This journal may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Published by Prepress Projects Ltd, Perth, Scotland ( on behalf of NETSCC, HTA. Printed on acid-free paper in the UK by Charlesworth Press. G

5 DOI: /hta16240 Health Technology Assessment 2012; Vol. 16: No. 24 iii Abstract Screening for cystic fibrosis-related diabetes: a systematic review N Waugh, 1,3 * P Royle, 1,3 I Craigie, 4 V Ho, 1 L Pandit, 1 P Ewings, 5 A Adler, 6 P Helms 2 and C Sheldon 7 1 Department of Public Health and 2 Department of Child Health, University of Aberdeen, Aberdeen, UK 3 Warwick Evidence, Warwick Medical School, Warwick, UK 4 Childrens Diabetes Service, Royal Hospital for Sick Children, Glasgow, UK 5 Research Design Service, Musgrave Park Hospital, Taunton, UK 6 Addenbrookes Hospital, Cambridge, UK 7 Royal Devon and Exeter Hospital, Exeter, UK *Corresponding author Background: Cystic fibrosis (CF) is an inherited disease that leads to damage to lungs, pancreas and other organs. Most people with CF die prematurely from lung disease, but survival has improved markedly over the decades and it is estimated that children born with CF now will live to an average age of 50 years. CF-related diabetes (CFRD) is due to damage to the pancreas, which, over time, loses its capacity to produce sufficient insulin. CFRD is becoming more common owing to the improved survival of people with CF. Objectives: The initial aim was to review the methods for screening for CFRD, which can be symptomless but still be causing harm. As the aim of screening and early detection is to allow earlier treatment, a second aim was to assess the effectiveness of treatments. However, during the review it became clear that there were problems with how CFRD is defined, uncertainty about when hyperglycaemia should be treated. Data sources: Details of relevant studies were obtained from the usual bibliometric databases MEDLINE ( ), EMBASE ( ), The Cochrane Library (all sections), Web of Science ( ). Websites of relevant bodies were searched for guidelines and reports. Conference abstracts were searched. Expert co-authors identified key papers. Review methods: Systematic reviews of treatments and screening tests. Screening studies were data extracted if they provided sufficient data to construct 2 2 tables. Other screening studies were described in narrative manner. The background to CF and CFRD were described in a narrative manner, as was Chapter 2 on problems with defining CFRD. A model was constructed for cost-effectiveness analysis, but was not used because of lack of data. Results: Diabetes is usually defined based on the level of blood glucose (BG) at which the risk of retinopathy occurs. For CFRD, it would be better to define it on the level at which the risk of lung disease (pulmonopathy) rises. There seems little place for treatments other than insulin, but the best insulin regimen remains to be confirmed. The best screening test may be by continuous glucose monitoring systems but further evidence is required. Screening may need to detect BG levels of > 8 mmol/l because that may be the level above which pulmonopathy starts in people with CF. Queen s Printer and Controller of HMSO This work was produced by Waugh et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

6 iv Abstract Limitations: The evidence base for treatment is disappointing with few large randomised controlled trials. The key question is when treatment should start, perhaps at the postprandial hyperglycaemia stage. Research is needed. Until that is done, we cannot be sure what we are screening for, and, therefore, which screening strategy should be used. Conclusions: The definition of CFRD should probably be based on pulmonopathy risk, rather than using the classical definition of diabetes. That implies that we should be screening for a wider range of hyperglycaemia than in other forms of diabetes, perhaps to detect BG excursions of > 8 mmol/l. Insulin treatment may need to start at lower levels than formerly accepted. Funding: The National Institute for Health Research Health Technology Assessment programme.

7 DOI: /hta16240 Health Technology Assessment 2012; Vol. 16: No. 24 v Contents List of abbreviations Executive summary vii ix 1. Introduction 1 Cystic fibrosis 1 Cystic fibrosis-related diabetes 4 Lung function in diabetes mellitus 7 Terminology 9 Decision analysis Defining cystic fibrosis-related diabetes 13 How are impaired glucose tolerance and diabetes mellitus currently defined and classified? 13 When does diabetes start? 14 World Health Organization American Diabetes Association criteria for the diagnosis of diabetes mellitus 15 How are cystic fibrosis-related impaired glucose tolerance and cystic fibrosis-related diabetes currently defined and classified? 15 Biochemical thresholds for glucose in cystic fibrosis-related diabetes 16 The effect of impaired glucose metabolism in cystic fibrosis 16 Effect on the lungs 17 Other effects of insulin deficiency 20 Conclusions Treatment of hyperglycaemia in cystic fibrosis 21 Introduction 21 Identification of treatment studies 21 Studies of treatment of cystic fibrosis-related diabetes 23 Can we quantify the utility of insulin treatment? 36 Overview of review articles of cystic fibrosis-related diabetes treatment 37 Discussion 48 Conclusions Systematic review of screening tests 51 Terminology 51 Background 52 Methods 53 Results 58 Other studies 62 Discussion 66 Conclusion Health economics 69 Modelling approach 69 Screening 70 Screening model 71 Queen s Printer and Controller of HMSO This work was produced by Waugh et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

8 vi Contents Other screening tests 72 What are we screening for? 73 Other problems with modelling 73 Quality-of-life studies in cystic fibrosis and cystic fibrosis-related diabetes Discussion 77 Statement of principal findings 77 How sensitive do we need screening to be? 77 Question: What time of day to test? 78 Question: Does isolated postprandial hyperglycaemia do harm? 78 Question: At what age should screening start? 78 Question: Might there be an age at which screening could be reduced? 79 Question: Does screening for cystic fibrosis-related diabetes and impaired glucose tolerance meet the criteria of the National Screening Committee? 79 Conclusions 82 Research needs 82 Acknowledgements 85 References 87 Appendix 1 Details of search strategy and PRISMA flow diagram 103 Appendix 2 Studies of treatment of cystic fibrosis-related diabetes and cystic fibrosis with non-diabetic hyperglycaemia 107 Appendix 3 The quality assessment of diagnostic accuracy studies tool to assess the quality of diagnostic accuracy studies 119 Appendix 4 Data extractions of diagnostic studies 121 Appendix 5 Reasons for exclusion of screening studies 149 Appendix 6 Quality-of-life studies not mentioning cystic fibrosis-related diabetes but with cystic fibrosis-specific measures 151 Appendix 7 Ongoing studies 155 Appendix 8 Project description from original grant application 161 Health Technology Assessment programme 175

9 DOI: /hta16240 Health Technology Assessment 2012; Vol. 16: No. 24 vii List of abbreviations %FEV 1 %FVC ADA AUC BDI BG BGP BMI CBGM CF CFQ CFQoL CFRD CFRD FH CFRIGT CFTR CGM CGMS CHQ CI CSII DECODE DKA DQoL EASD EHS EQ-5D EQ-5D-Y FEV FEV 1 FH FOGTT FPG FPIR FVC GCT HTA IFG IGT INDET ISPAD MDI NDDG NGT NHA NHANES NICE per cent predicted forced expiratory volume in 1 second per cent predicted forced vital capacity American Diabetes Association area under the curve Beck Depression Inventory blood glucose blood glucose profiling body mass index continuous blood glucose monitoring cystic fibrosis Cystic Fibrosis Questionnaire Cystic Fibrosis Quality of Life cystic fibrosis-related diabetes cystic fibrosis-related diabetes without fasting hyperglycaemia cystic fibrosis-related impaired glucose tolerance cystic fibrosis transmembrane conductance regulator continuous glucose monitoring continuous glucose monitoring system Child Health Questionnaire confidence interval continuous subcutaneous insulin infusion Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe diabetic ketoacidosis Diabetes Quality-of-Life measure European Association for the Study of Diabetes Edinburgh Hypoglycaemia Scale European Quality of Life-5 Dimensions EQ-5D version for children and adolescents forced expiratory volume forced expiratory volume in 1 second fasting hyperglycaemia full oral glucose tolerance test fasting plasma glucose first-phase insulin response forced vital capacity glucose challenge test glycated haemoglobin Health Technology Assessment impaired fasting glucose impaired glucose tolerance intermediate hyperglycaemia with normal FPG and 2-hour PG International Society for Pediatric and Adolescent Diabetes multiple daily injection National Diabetes Data Group normal glucose tolerance natural history arm National Health and Nutrition Examination Survey National Institute for Health and Clinical Excellence Queen s Printer and Controller of HMSO This work was produced by Waugh et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

10 viii List of abbreviations NIH NPH NPV NSC OGTT OHA PAF PFT PG PPH PPV QALY QoL QUADAS QWB RBG RCT ROGTT SD SF-36 SIGN SIP SS T1DM T2DM VAS WHO WtSDS National Institutes of Health neutral protamine Hagedorn negative predictive value National Screening Committee oral glucose tolerance test oral hypoglycaemic agent population attributable fraction pulmonary function test plasma glucose postprandial hyperglycaemia positive predictive value quality-adjusted life-year quality of life quality assessment of diagnostic accuracy studies Quality of Well-Being scale random blood glucose randomised controlled trial reduced oral glucose tolerance test standard deviation Short Form questionnaire-36 items Scottish Intercollegiate Guidelines Network Sickness Impact Profile Shwachman clinical score type 1 diabetes mellitus type 2 diabetes mellitus visual analogue scale World Health Organization weight standard deviation score All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices, in which case the abbreviation is defined in the figure legend or in the notes at the end of the table.

11 DOI: /hta16240 Health Technology Assessment 2012; Vol. 16: No. 24 ix Executive summary Background Cystic fibrosis (CF) is caused by a genetic defect. The defective gene has to be inherited from both parents. CF occurs in about 1 in every 2500 births in the UK. The effect is to make some normal bodily fluids much thicker and more viscous than usual, and this affects particularly the lungs and the digestive system. The lungs become prone to infection and subsequent damage, and the main cause of death in cystic fibrosis is respiratory failure. The pancreas is also affected, particularly the β-cells that produce insulin. Over time, many people with CF develop cystic fibrosis-related diabetes (CFRD) due to insulin deficiency. Treatment of CF has improved and survival has greatly improved. Over decades, CF has changed from a disease that was normally fatal in childhood, to one in which most patients survive into adulthood. Because survival is now much better, more people with CF live long enough to develop diabetes. About half of people with CF now live to about 40 years of age. It has been estimated that children born in 2000 with CF will, on average, live to reach the age of 50 years. Patients with CFRD do not live as long as those with CF who do not develop CFRD. The onset of CFRD is insidious, and there may be none of the classical symptoms of diabetes. However, the diabetes may be causing harm, such as promoting colonisation of the lungs with harmful bacteria. Objectives Methods The primary objective of this review was to identify the most clinically effective and cost-effective way of screening for CFRD. As the aim of screening would be earlier diagnosis and treatment of CFRD, a secondary objective was to review the evidence on treatment at different stages. However, it became clear that there were problems with the definition of CFRD, and so we examined how CFRD was currently defined and considered alternatives. We started from the position that insulin treatment was beneficial in CFRD (compared with no treatment) and so the review of treatment focused on two main questions: 1. Are oral glucose-lowering agents useful? 2. Are any treatments beneficial at lesser stages of hyperglycaemia, such as impaired glucose tolerance (IGT), i.e. when should treatment start? We carried out systematic reviews of studies of treatment of, and screening tests for, CFRD. We used a highly sensitive search strategy in order to capture all relevant studies, with no restriction on study type or language. We searched MEDLINE, EMBASE, Web of Science, ISI Proceedings, and the Cochrane Central Register of Controlled Trials. Auto-alerts were run in MEDLINE and EMBASE from May 2008 to December Reference lists of included studies and relevant review articles were scanned. The internet was searched for grey literature, including websites of the Cystic Fibrosis Trust (UK) and similar organisations in other countries. We searched Queen s Printer and Controller of HMSO This work was produced by Waugh et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

12 x Executive summary meeting abstracts of Diabetes UK, American Diabetes Association, European Association for the Study of Diabetes, European Cystic Fibrosis Society, Annual North American Cystic Fibrosis meetings, and International Society for Pediatric and Adolescent Diabetes up to For research in progress, we searched ClinicalTrials.gov, Controlled-trials.com and the UK Clinical Research Network. We also searched for studies of the economics of CFRD, including quality-of-life (QoL) studies, with a view to populating a decision tree economic model. We used the software package Simul8 (Simul8 Corporation, Boston, MA, USA) to create a model. Screening studies were included in the systematic review if they provided sufficient detail for the construction of 2 2 tables for calculating sensitivity and specificity. Other studies were included in a narrative section. We looked for results for both CFRD and for the IGT stage. Results Diagnosis of cystic fibrosis-related diabetes The commonest forms of diabetes are type 1 (T1DM, formerly called insulin-dependent diabetes) and type 2 (T2DM, formerly called non-insulin-dependent diabetes). These are defined in terms of the level of blood glucose (BG) above which diabetic eye disease retinopathy occurs. Cystic fibrosis-related diabetes is a distinct type of diabetes, due to a slowly progressive loss of the insulin-producing β-cells in the pancreas. The organ most at risk in CF is the lung, and as hyperglycaemia has several adverse effects on the lung, our conclusion from review of the literature is that CFRD should be defined according to the level at which lung damage ( pulmonopathy ) occurs, an early manifestation of which may be weight loss. The lung secretions are usually very low in glucose, but if BG is high there may be more glucose in the lung secretions than usual, and this may promote microbial colonisation at levels well below the diabetes level, perhaps starting around 8 mmol/l. This has implications for choice of screening test, as it suggests that we should be screening for, and intervening at, the IGT stage. It may be that intervention should start earlier, at the stage of postprandial hyperglycaemia (PPH) [i.e. plasma glucose (PG) high at 1 hour but normal by 2 hours after meals or the oral glucose tolerance test (OGTT)]. Treatment The evidence base on treatment was poor, with few trials. Most evidence came from small case series, usually of short duration. There were seven studies of oral agents. There was some evidence that sulfonylureas had some effect. One trial used acarbose, but only for 2 weeks, and adverse effects were a problem. One good-quality (although possibly underpowered) trial compared insulin and the short-acting insulin secretagogue repaglinide. Insulin was more effective in improving body mass index (BMI), with an increase of 0.39 kg/m 2, compared with a non-significant rise of 0.15 kg/m 2 in the repaglinide group. There was no difference in the level of glycated haemoglobin ( ). There were no trials of the newer agents: the glucagon-like peptide 1 (GLP-1) analogues (exenatide, liraglutide) or the dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g. sitagliptin, vildagliptin). In the case of the GLP-1 analogues, the initial nausea they cause would be undesirable in a group characterised by low BMI.

13 DOI: /hta16240 Health Technology Assessment 2012; Vol. 16: No. 24 xi In summary, oral agents did not appear useful and international guidelines do not support their use. Insulin is the treatment of choice. The insulin studies were also disappointing, with only one trial comparing different insulins. This trial compared glargine and neutral protamine Hagedorn (NPH) insulins, and found little difference. There were no differences in or postprandial BG levels, but fasting PG was slightly lower with glargine (2 mg/dl lower, statistically but not clinically significant), and the glargine group gained 1 kg more in weight than the NPH group (not statistically significant, although with only 19 patients in the study, statistical power was low). The study was not blinded and was funded by the manufacturer of glargine. Two studies used continuous subcutaneous insulin infusion (CSII), which might be beneficial by providing greater flexibility, but they were uncontrolled case series with small numbers (three and nine subjects). Most studies of insulin treatment measured outcomes before and after starting insulin. Five studies examined insulin treatment at the IGT stage, but some had very small numbers (3, 6 and 9 subjects). Two studies (with 54 and 6 subjects) reported that the decline in forced expiratory volume (FEV) was halted or reversed by insulin treatment. One study with 13 patients reported a reduction in pulmonary exacerbations. Two were inconclusive. Only one study was a randomised controlled trial. Most were available only as abstracts, with little detail. One before-and-after study with only four patients suggested that treatment at the PPH stage might be useful, with improvements in weight ranging from 0.7 kg to 5.7 kg on doses of insulin ranging from 6 to 12 units daily, and also improvements in FEV. Screening for cystic fibrosis-related diabetes We used the 75-g OGTT as the reference standard. Most studies reported only the fasting and 2-hour glucose levels. The full OGTT (FOGTT) includes measurements at baseline and at 30, 60, 90 and 120 minutes after an oral glucose load. Most studies used or fasting plasma glucose (FPG). These tests did not appear satisfactory for detecting either CFRD or IGT, because their sensitivity was poor. However, this depended on cut-off levels chosen, and, as expected, higher sensitivity tended to be achieved at the cost of poorer specificity. Sensitivities ranged from 23% to 100% with, and from 25% to 70% with FPG. Sensitivity was better when the aim was to detect CFRD rather than both CFRD and IGT. There were few studies of newer methods, such as continuous glucose monitoring systems (CGMSs) and profiles (a series of BG measurements over the course of the day) but they appeared to be more useful, especially for detecting hyperglycaemia, which occurs more often at certain times of day, such as during the evenings. CGMSs may become the method of choice. The most sensitive test may be the 1-hour postprandial glucose, but evidence is lacking on the benefits of treatment if that is the only abnormality. This could be measured by two tests: the 50-g glucose challenge test (GCT) or the FOGTT. There is some evidence that treatment is beneficial at the IGT stage, and we conclude that screening should be for both CFRD and IGT. Queen s Printer and Controller of HMSO This work was produced by Waugh et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

14 xii Executive summary Quality of life in cystic fibrosis-related diabetes There was very little evidence on QoL in CFRD, but more on QoL in CF. The effect of CFRD appeared to be less than the effect of T1DM, but the one study that reported this had a low response rate. Modelling We constructed a model with arms for no screening, and for different screening tests, but there were insufficient data to populate it. We have listed the data required. In the no-screening arm, there would be three groups: (1) those who never develop diabetes; (2) those who develop symptomatic diabetes and are treated; and (3) those who develop diabetes but are never diagnosed, who die earlier than they would have done had they been treated. The most important gap in the evidence concerns the level at which hyperglycaemia in CF should be treated. Other gaps include expected survival in those in the age group that would be screened (probably years), and the number of life-years lost owing to CFRD, which could be as much as 11 years. Conclusions The evidence base in CFRD is disappointing. There is some evidence that harm to pulmonary function occurs at BG levels below those used for defining other types of diabetes, and perhaps around the 8-mmol/l level, with episodic PPH being harmful to the lung by promoting colonisation and infection. As diseases should be defined based on the harm they do, CFRD should be defined according to the level at which pulmonary harm occurs, and not by the same thresholds of PG as are used for T1DM and T2DM. Screening for CFRD is justified, but the case for screening for lesser degrees of hyperglycaemia is less strong. The highest research priority is for a trial of starting insulin treatment at different stages of hyperglycaemia, starting with PPH, diagnosed by 1-hour glucose challenge, or by CGMSs or serial profiles. Outcomes should include weight and lung function, not just glycaemic control. If our hypothesis is correct, i.e. that transient hyperglycaemia exceeding 8 mmol/l is harmful to the lung, then treatment at the stage of isolated PPH would be beneficial for lung function. Trials should be of adequate duration, of at least several years. Trials of different insulin regimens are required. These could include a basal insulin, compared with short-acting meal-time insulins alone (especially as in the early stages hyperglycaemia is mainly postprandial) and (perhaps at later stages) CSII. More data are required on the relative merits of NPH, glargine and detemir, particularly in view of the cost differences. Given the considerable treatment burden associated with CF and CFRD, the impact of different regimens and screening methods needs to be assessed. More evidence on the relative merits of the 1-hour GCT, CGMSs and serial profiles is required, with the aim being to detect any hyperglycaemia > 8 mmol/l. In the longer term, we need to find out if pancreatic damage can be prevented and diabetes avoided or delayed.

15 DOI: /hta16240 Health Technology Assessment 2012; Vol. 16: No. 24 xiii Funding Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research. Queen s Printer and Controller of HMSO This work was produced by Waugh et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

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17 DOI: /hta16240 Health Technology Assessment 2012; Vol. 16: No Chapter 1 Introduction Cystic fibrosis Cystic fibrosis (CF) is a disease that was first described in 1936 by Guido Fanconi. 1 It is an autosomal recessive disease that can present at any age, but is more commonly diagnosed in early childhood. 2,3 Screening for CF is offered to all babies in Scotland, England, Wales and Northern Ireland. A systematic population antenatal screening is not recommended in the UK but this is currently under review. 4 The defective gene causes faulty transport of sodium chloride in the body, leading to thick viscous secretions, mainly affecting the lungs and the digestive system. 5 CF affects the lungs, pancreas, liver and intestines, and the process involved eventually leads to multisystem organ failure. According to the Cystic Fibrosis Trust, there are over 8500 people in the UK with CF, the severity of which varies from person to person and changes throughout their life. 6 For example, a person with CF may initially have a good quality of life (QoL), where little physiotherapy is required and they are able to play sports, but then recurrent chest infections can lead to deterioration in respiratory function. There have been major advances in management of, and outcomes from, CF over recent decades. Littlewood has provided a valuable history of the disease, noting that in the course of a professional lifetime, CF has changed from being regarded as almost always fatal in early childhood to a disease in which the aim now is striving to maintain the affected person in the best possible condition to reach adulthood with minimal respiratory and nutritional damage (J Littlewood, Cystic Fibrosis Trust, 2010, personal communication; comment was previously in a historical account on the Cystic Fibrosis Trust website). Epidemiology The prevalence and distribution of the gene varies among ethnic groups, 5 with Caucasians having a higher probability of carrying the abnormal gene. 7 Table 1 shows the incidence of CF in various populations. The incidence in the Caucasian population is approximately 1 : , 5 with a carrier frequency of 1 in 25 live births. 7 Ashkenazi Jews and non-hispanic Caucasians also have a carrier rate of 1 in 25 live births, which is higher than the carrier rate in other ethnic groups; 11 Hispanic Americans have a carrier rate of approximately 1 in 46, African Americans have a carrier rate of 1 in 62, and for Asian Americans the carrier rate is 1 in There are quite large variations in incidence within Europe, ranging from a high of 1 in 1353 births in Ireland to 1 in 25,000 in Finland. 12 Within countries, there are sometimes populations or areas of much higher incidence, such as: 13 North Brittany 1 in 377 births The Amish in the USA 1 in 569 births Saguenay Lac-Saint-Jean, Quebec 1 in 902 births. The incidence rate in the UK is 1 in 2500 live births. 8 Queen s Printer and Controller of HMSO This work was produced by Waugh et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

18 2 Introduction TABLE 1 Incidence of CF in different populations Country/regions Incidence per live births Scotland 8 1/1984 Ireland 5 1/1700 Brittany 5 1/1700 Australia 5 1/3500 Finland 5 1/25,000 to 1/40,000 Estonia 5 1/7750 UK 9 1/2415 USA 5 1/2000 1/4000 African Americans 5 1/17,000 South America 5 1/9000 China 10 Very rare Genetics A gene defect occurs on chromosome 7, which affects the production of a protein called cystic fibrosis transmembrane conductance regulator (CFTR). This dysfunctional chloride channel affects the water and electrolyte composition of secretions from various places including the pancreatic ducts and airways. This leads to an accumulation of thick viscous secretions 7 and eventually destruction of the affected organs. 8 Many genes can cause CF. They are grouped into five classes, as follows: 14 class I defective protein production; few or no functioning CFTR chloride channels class II defective processing, so that CFTR does not reach the surface membrane where it normally functions class III defective regulation, but it does reach its site of action class IV defective conductance CFTR is in the right place, but the channel fails to conduct properly class V reduced amounts of functional CTFR protein. The less functioning CFTR there is, the more severe the phenotype. Classes I III are associated with more severe disease and higher mortality. Class II is by far the most common type in the UK. The commonest mutation is delta F508 (ΔF508). There are international variations in the frequency of mutations which can affect the severity of CF and the prevalence of cystic fibrosisrelated diabetes (CFRD). For example, in the Netherlands, the second commonest mutation is A445E, which is associated with milder disease. 3 There are over 1000 relevant mutations, some of which cause mild disease. Pathology The build-up of viscous secretions in the lungs means that patients are prone to repeated infections by organisms such as Staphylococcus aureus, Haemophilus influenzae and Pseudomonas aeruginosa. 5 Owing to the stasis of the secretions, bacterial clearance is reduced and inflammatory lung damage ensues. 5 Once severe lung disease is established, lung transplantation is required and if this cannot be carried out, respiratory failure occurs, which eventually leads to death.

19 DOI: /hta16240 Health Technology Assessment 2012; Vol. 16: No The effect on the pancreas causes deficiency of digestive enzymes, leading to malabsorption of undigested foods and undernutrition. Although the primary defect is of exocrine secretion, the islet cells that are initially preserved may become damaged with time, thereby leading to a decrease in insulin and glucagon secretion. Other recognised problems include hepatic cirrhosis and infertility in males. Management Management is complex and includes daily bronchial drainage by physiotherapy, nebulised bronchodilators and mucolytics, chronic suppressive antibiotics if infected, anti-inflammatory therapy, nutritional support (such as pancreatic enzymes and vitamin supplements), and frequent monitoring of pulmonary function and microbial carriage. 15 Treatment imposes a significant burden on most people with CF. This burden may include getting up at 6.30 am every day so that physiotherapy can be carried out before going to school, ingesting enzymes after consuming any amount of food (e.g. a biscuit), and more physiotherapy in the evenings before going to bed. 6 Treatment is generally tailored to the individual but the constant ingestion of medication and the rigid treatment schedule removes the spontaneity and pleasure of life in general. The burden has been quantified by Sawicki et al. 16 in the Project on Adult Care in CF (PAC-CF) carried out in 10 centres in the USA. The median number of daily therapies was seven, and an average of 108 minutes a day was spent on treatment. Common medications were pancreatic enzymes (taken by 85%), β-agonist bronchodilators (65%), anti-reflex agents (50%), DNase (49%) and azithromycin (47%). Ninety-three per cent were on at least one nebulised medication. Prognosis In 1938, Andersen 17 was the first person to give a comprehensive description of CF. Over 70% of the 49 patients examined in her study died before their first birthday. In the mid-1950s, few children with CF would live to attend elementary school. 18 Dodge et al. 19 reported that over the period , the average per cent surviving by age were 97% to age 10 years, 90% to age 20 year, 63% to age 30 years and 45% to age 40 years. However, median survival has been steadily improving. In the UK, median survival was 38.8 years in 2008; % of those on the register were aged 20 years or over. In the USA, the median predicted survival in 2007 was 37.4 years. 18 One feature associated with this is the improvement in lung function, with the proportion of 18-year-olds with good lung function [forced expiratory volume in 1 second (FEV 1 ) > 70% predicted] increasing from around 32% in 1985 to near 70% in Most people with CF die of lung disease. The improvement has not applied at all ages. Kulich et al., 21 using US Cystic Fibrosis Foundation Patient Registry data on 31,012 patients with 5234 deaths from 1985 to 1999 (17% of the cohort), reported that mortality had fallen by 61% in the age range 2 5 years, by 70% in the range 6 10 years and by 45% in the range years. 21 Females had poorer survival. There was little improvement in the over-20s but, as the authors note, this may have been because some who would have died before reaching 20 years were now surviving past it, but not for very long. In the UK, Lewis et al. 22 also noted an increase in survival only up to the age of 20 years. In the UK, Dodge et al. 23 reported that CF was no longer an important cause of death in children. With better treatment now available, it is estimated that a child born with CF in 2000 would live to approximately 50 years of age. 19 Queen s Printer and Controller of HMSO This work was produced by Waugh et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

20 4 Introduction As a result, an increasing proportion of people with CF are adults. In the USA in 1990, about 30% of the patients in the US Cystic Fibrosis Foundation Patient Registry were 18 years or older; in 2008, that figure had reached 46%. 18 One consequence of this is that many women with CF are living to have children of their own. A UK survey by Edenborough et al. 24 reported 48 live births from 72 pregnancies, with almost half of the births being premature. However, a French study reported 64 live births from 75 pregnancies, with only 18% being premature. 25 Gestational diabetes is common, with McMullen et al. 26 reporting a baseline diabetes prevalence of 9%, rising to 21% during pregnancy, in a group of women whose age ranged from 15 to 38 years (median 24 years). McMullen et al. 26 did note that the high prevalence seen in pregnancy might reflect the more thorough screening during pregnancy. In the UK, the 2008 Cystic Fibrosis Trust Annual Data Report, using a slightly different age breakdown, showed that 43.8% of people with CF were aged 20 years or over. 20 In Canada, similar improvements have been reported, with (rounded) median survival being 24 years in 1982, and 29, 34, 33 and 37 years in 1987, 1992, 1997 and 2002, respectively, reaching 48 years in The severity of CF can be assessed by the Shwachman clinical score (SS), which allocates points for general activity, physical examination, nutritional status and radiographic findings with a score out of 100, with severe disease having a score of < Most deaths are due to lung damage. 29 Cystic fibrosis-related diabetes Diabetes mellitus was first described as a complication of CF in The incidence of diabetes is related to the duration of CF, and with the significantly improved survival into adulthood, more patients are living long enough to develop diabetes. Thus, a higher proportion of patients with CF will develop diabetes than would have done in the past. Epidemiology The prevalence of CFRD increases with age and occurs in up to 40% of patients with CF by the fourth decade of life. 31 The risk factors for developing CFRD are increasing age, genetic factors, pancreatic insufficiency, pulmonary infections, corticosteroid therapy and supplemental nutrition. 1 The median age at onset of CFRD is 20 years, and females tend to develop this disease at a younger age than their male counterparts. 1 In one study of 448 patients with CF, the median age at onset of CFRD was reported as approximately 20 years (18.7 years for females and 21 years for males). 32 The prevalence of CFRD has been variably reported and increases with age owing to the natural progression of impaired glucose metabolism. Lanng et al. 33 reported a CFRD prevalence of 1%, 30%, and 75% in those under 10, at 20 and at 30 years of age, respectively. 33 In a recent UK-based prospective study, Adler et al. 34 reported the incidence of CFRD as 3.4% per year. The definition of diabetes that was used included physician diagnosis, a 2-hour post glucose load blood glucose (BG) concentration of > 11.1 mmol/l or treatment with insulin or oral hypoglycaemic agents (OHAs). Rosenecker et al. 35 reported that CFRD was more common in females, with, for example, prevalence in the age range of years being 6% in males and 17% in females. Although the aetiology of this is unknown, it may be due to the earlier onset of puberty in girls. 7 There is also a greater prevalence of CFRD in females. 36 Figure 1 shows the prevalence of CFRD

21 DOI: /hta16240 Health Technology Assessment 2012; Vol. 16: No Per cent (%) % 9% 5 9 (n = 26) 38% 26% (n = 89) 42% 27% 35% (n = 81) 43% 30+ (n = 46) CFRD IGT Age group (years) FIGURE 1 Cystic fibrosis-related diabetes prevalence. Redrawn from Moran et al. (1998). 37 and impaired glucose tolerance (IGT) for both sexes in various age groups. 37 Here, it can be seen that in the over-30s, > 40% have diabetes and nearly 30% have IGT. The UK Cystic Fibrosis database 7 reported that 39% of those > 10 years and who had been tested were diabetic. For the over-30-year-olds it was 59%; 47% of the over-10s had not been tested. In the 15-year-olds, 9% had diabetes and another 8% were classed as glucose intolerant. The Cystic Fibrosis Foundation (CFF) 2008 annual data report 18 showed that in the USA the prevalence of CFRD reached a plateau in the 35- to 44-year age range, with about 32% having CFRD. This may imply that screening for diabetes could stop after the age of 40 years, because those who are going to develop diabetes will have done so by then. A more recent update from the USA from Moran et al., 38 based on the Minnesota data, reported that CFRD was present in 2% of children (< 10 years), 19% of adolescents (11 17 years) and 40 50% of adults. The younger patients tended to have CFRD without fasting hyperglycaemia (FH), but with age the proportion with FH rose to about half in the years age group and about two-thirds in the over-40s (estimated from graph). A higher proportion of women than men in the years age range had CFRD: about 60% versus 40%. In Australia, Rana 39 reported that the incidence of reported CFRD in the under-18-year age group had risen from 0.6 per 10 6 in 2000 to 6.7 per 10 6 in 2008, although this may be due to better detection, as 53% were diagnosed by oral glucose tolerance test (OGTT) in compared with 5% in earlier years. Mackie et al. 1 stated that in the UK the prevalence of CFRD has risen from 3 10% in 1969 to 14 30% in the early 1990s, based on differing screening methods. Droumaguet et al. 40 in Paris reported a prevalence of 36% among 243 adults with CF, but their cohort was somewhat unusual in having a mean age at diagnosis of CF of 21.5 years. The mean age at onset of CFRD was 27 years (range years). In Denmark, Lanng et al. 33 demonstrated a prevalence of 24% for all ages, rising to 34% in those aged 10 years and above. In the USA, Moran et al. (2009) 38 reported an overall prevalence of 33%, with the highest prevalence of just under 50% in the 30- to 39-year age group (from graph, figure 1a). Queen s Printer and Controller of HMSO This work was produced by Waugh et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

22 6 Introduction In Canada, only 21% had developed CFRD by age of 35 years and over and the prevalence had reached a plateau after the age of 25 years. 27 Table 2 shows the prevalence of CFRD at different age groups in various different countries. Genetics The risk of CFRD varies among the five classes of CF. Unfortunately, the risk is highest in the commonest classes, II and III, with 22% of these adults being diabetic, compared with < 2% in classes IV and V. 14 In the UK, Adler et al., 42 using UK CF Registry data on a large cohort, found that the incidence of CFRD was 3.5% a year, and was highest in those with CFTR class I and II mutations. About 80% of UK patients have class II mutations. The ΔF508 mutation appears to increase the risk of CFRD, whereas the N1303K mutation may reduce the risk. 43,44 In populations with low prevalence of ΔF508, such as in Brazil, CFRD is less common. 45 There appears to be a small subgroup with adult onset and a milder form of CF, with a low prevalence of CFRD. Gilljam et al. 46 in Toronto reported 7% of their adult patients to be in this group. 46 The risk of CFRD may be increased if there is a family history of type 2 diabetes mellitus (T2DM), possibly because a gene linked to T2DM increases the risk and lowers the age of onset of CFRD. 47 Pathology Endocrine function In CF, the abnormal function of CFTR leads to the production of viscous secretions and this causes obstructive damage to the pancreas. 7 Fibrosis and fatty infiltration of the pancreatic exocrine glands occur and disrupt the islet architecture. Many, but not all, of the islet cells are destroyed and this leads to a progressive loss of endocrine cells, 7,15 the main cause of CFRD. 48 Whole islets are destroyed, unlike the β-cell-specific obliteration seen in type 1 diabetes mellitus (T1DM), 49 leading to the damage of α-cells, β-cells and pancreatic polypeptide-producing cells. This leads to a reduction in glucagon, insulin and pancreatic polypeptide secretions, respectively. 7 By the time of diagnosis, there has been a loss of 50% of β-cell mass, similar to that seen in T2DM. 50 In addition, amyloid deposits are found within the β-cells. However, it is not clear if the amyloid accumulates during the disease process or even if it contributes to β-cell dysfunction. 36 Cystic fibrosis-related diabetes is described more fully in Chapter 2. The precise mechanism of CFRD is unclear. 1 CFRD is characterised by an insulin deficiency 7 owing to the loss of insulin-producing β-cells. 31 Couce et al. 50 state that there is approximately TABLE 2 Prevalence of CFRD at different ages in different countries Country Under-12s Adolescents Young adults Adults 30 years and over UK 41 0% for 9 years 5% for years 10% for years 16% Denmark 33 34% for years 53% for 20 years USA 38 2% for < 11years 19% for years 40% for years 45 50% Mid-Europe 35 1% < 11 years 8% for years 12% years 15% for 26 years The Netherlands 3 22% for years 36% for years 50% for 31 years Canada 2007 registry 27 1% < 11 years 5% years 14% years 20% years, 21.5% 35 years